Clinical Protocol (NHLBI 06-H-0072): Atorvastatin as a disease-modifying agent in Stage II and Stage III Pulmonary Sarcoidosis: A randomized, double-blinded, placebo-controlled trial. Some Biospecimens will also be collected/stored under the NHLBI Clinical Protocol 96-H-100. PI: Joseph Fontana, Staff Physician, PVMB Purpose of protocol (Precis): Sarcoidosis is a multi-system granulomatous inflammatory disease. Pulmonary involvement is most common. Patients typically experience fatigue, weakness and dyspnea. Respiratory muscle weakness, which may be secondary to granulomatous inflammation, is associated with dyspnea and decreased quality of life (QOL). The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some patients, it can progress to pulmonary fibrosis and death. Granulomatous inflammation is characterized primarily by accumulation of monocytes, macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, TNF-alpha,INF-gamma, IL-2, and IL-12, characteristic of a Th1-polarized response (T-helper lymphocyte-1 response). Corticosteroids are the current mainstay of treatment, but their long-term benefits are not certain. Because steroids often produce undesirable side effects, investigations to identify alternative therapies are warranted. There is sufficient evidence to test the proof of concept that pathways targeted by statins will have a therapeutic effect in sarcoidosis, since, in pre-clinical studies, statins blunt Th1-mediated inflammatory responses. Objectives: The objective of this protocol is to conduct a randomized, double-blind placebo-controlled, trial which aims to determine if atorvastatin administration results in less steroid use and longer steroid-free intervals in patients with pulmonary sarcoidosis who require prednisone treatment. The primary endpoint is the duration of the steroid-sparing period. Secondary clinical and physiological endpoints are intended to analyze possible anti-inflammatory and beneficial effects of the drugs. Since there is no gold standard outcome measure in sarcoidosis, four categories of secondary endpoints will be used to characterize the effects of the therapeutic agent on the clinical course of the disease: imaging (high resolution chest CT); quality of life assessments (SF-36 and SGRQ), anti-inflammatory effects (biomarkers and relapse rates), and functional effects (CPET, PFTs). Finally, we will study the utility of exhaled nitric oxide and carbon monoxide in monitoring disease activity. Reasons to continue the protocol: Sarcoidosis is a multi-system granulomatous inflammatory disease of unknown etiology. Pulmonary involvement is the most common manifestation. Patients typically experience cough, dyspnea, and fatigue. Disease progression can impair the quality of life and lead to end-stage pulmonary fibrosis and death. Corticosteroids are the current mainstay of treatment, but their long-term benefits are not certain, and their use is associated with a decrease in quality of life. Because steroids produce undesirable side effects, investigations to identify alternative therapies are warranted. While alternative therapies are available, none are FDA-approved. Most alternative therapies are not benign, and there are no long-term data supporting their use in pulmonary sarcoidosis. Given the limited options, none of which are ideal, (that is, highly effective agents with mild side-effect/toxicity profiles), patients, at their own risk, sometimes forego treatment altogether, to avoid the untoward effects of steroids or the alternative agents. Rigorous clinical trials are needed to determine whether anti-inflammatory agents can provide steroid-sparing benefits and improve therapy of pulmonary sarcoidosis. We have bolstered recruitment through new methods and efforts, as well as through sarcoidosis support groups. We are working to develop a good working relationship with a newly formed support group in Washington, D.C. In addition, we are exploring ways to collaborate with university programs and have added an Associate Investigator (AI) from Brigham and Womens Hospital. To continue to increase enrollment, the PI will give grand rounds presentations to update the local physician community on sarcoidosis and offer them the opportunity to refer patients to this NHLBI trial. Study information found on the NHLBI recruitment web site, has been very helpful. We think that the recruitment web site may be partly responsible for the increase in enrollment that has occurred during the past 6 months. In addition, we are exploring ways to increase the trials exposure through other web-based vehicles and NHLBI public service announcements. To support the activities of the clinical research nurse, we have recruited a post baccalaureate student volunteer with clinical trial recruitment experience and retained our experienced recruitment volunteer. Finally, we have streamlined and improved our evaluation and screening process. Progress achieved: Since the last continuing review (in October 2008), 13 subjects have been enrolled and 12 randomized, bringing the accrual to 37. One subject is scheduled for enrollment within the month, increasing accrual to 38. New candidates are coming for clinical screening. In addition, one previously screened candidate, who met entry criteria, but who declined enrollment due to personal reasons, is returning for reevaluation and may now be willing to enroll and initiate the study. By the end of October 2009, we project to have accrued approximately 40. Recruitment Data: Recruitment Parameters n Telephone Screening Questionnaires 762 Clinical Exams/Screens Completed 114 Accepted 40 Enrolled 37 Study Findings to Date: Thirty-seven subjects have been enrolled; 36 randomized, and started on study agent. Because the study is double-blinded, we cannot compare differences in treatment arms. Pulmonary sarcoidosis flares and prednisone usage are secondary endpoints, and thus far, we have observed the following: 13/22 evaluable subjects have flared; 3 of the 13 flared subjects had a second flare event. With each flare, there is a substantial increase in prednisone usage. Total number of subjects enrolled: 37 Total of subjects randomized to study agent: 36 Total number of subjects completed 1 year of study agent: 21 Total of currently active participants: 11 Total number of withdrawals: 4 Subject Accrual Table: 06-H-0072 American Indian or Alaskan Native Asian or Pacific Islander Black, not of Hispanic Origin Hispanic White, not of Hispanic Origin Other or Unknown Total Male 0 0 6 0 8 0 14 Female 0 0 9 0 14 0 23 Total 0 0 15 0 22 0 37 Subjects withdrawn from protocol: 4 Current risk/benefit analysis of the study: The research involves more than a minor increase over minimal risk to subjects. The research may provide direct benefit to individual subjects and may yield generalizable knowledge about the subjects disorder or condition.